2 5-bis(1-aziridinyl)-1 4-benzoquinone derivatives

ABSTRACT

NEW 2,5-BIS(1-AZIRIDINYL)-3,6-DISUBSTITUTED-1,4-BENZOQUINONE COMPOUNDS ARE PROVIDED HAVING THE FORMULA   1,4-DI(O=),2,5-DI(AZIRIDIN-1-YL),3-R1,5-R2-   2,5-CYCLOHEXADIENE   WHEREIN R1 IS ALKYL OF 1 TO 5 CARBON ATOMS AND R2 IS A 2-CARBAMOLYLOXYETHYL GROUP, THE ETHYL MOIETY OF WHICH MAY BE SUBSTITUTED WITH ALKYL OF 1 TO 5 CARBON ATOMS OR ALKOXY OF 1 TO 5 CARBON ATOMS AT 1-POSITON OR ALKYL OF 1 TO 5 CARBON ATOMS AT 2-POSITION; OR BOTH R1 AND R2 REPRESENT A 2-N,N-DI(ALKYL)-CARBAMOYLOXYETHYL GROUP HAVING 1 TO 5 CARBON ATOMS IN EACH ALKYL MOIETY, 2-HYDROXYETHYL OR 2-ALKOXYETHYL GROUP HAVING 1 TO 5 CARBON ATOMS IN TH ALKOXY MOIETY. THESE NEW BENZOQUINONE COMPOUNDS ARE PROVED TO EXERT AN EXCELLENT ANTILEUKEMIC ACTIVITY, FOR EXAMPLE, AS STUDIED ON LYMPHOID LEUKEMIA L 1210 IN MICE AND THUS THEY CAN BE USED FOR HUMAN BEINGS AS A DRUG FOR THE REMISSION AND TREATMENT OF VARIOUS TYPES AND SEVERITIES OF LEUKEMIA. THEY ARE PREPARED FROM THE CORRESPONDING 1,4-BENZOQUINONE COMPOUNDS BY THE REACTION WITH AZIRIDINE.

3,631,026 2,5-BIS(l-AZIRIDINYL)-1,4-BENZOQU1NONE DERIVATIV S Hideo Nakao, Masao Arakawa, and Takahiro Nakamura, Tokyo, Japan, assignors to Sankyo Company Limited,

Tokyo, Japan No Drawing. Filed Jan. 23, 1969, Ser. No. 793,564 Claims priority, application Japan, Jan. 29, 1968, 43/5,315; Dec. 28, 1968, 44/331 Int. Cl. (307d 23/ 06 US. Cl. 260-239 EQ 10 Claims ABSTRACT OF THE DISCLOSURE New 2,5-bis(1-aziridinyl) 3,6-disubstituted-1,4-benzoquinone compounds are provided having the formula wherein R is alkyl of 1 to carbon atoms and R is a Z-carbamoyloxyethyl group, the ethyl moiety of which may be substituted with alkyl of 1 to 5 carbon atoms or alkoxy of 1 to 5 carbon atoms at l-position or alkyl of 1 to 5 carbon atoms at 2-position; or both R and R represent a 2-N,N-di(alkyl)-carbamoyloxyethyl group having 1 to 5 carbon atoms in each alkyl moiety, 2-hydroxyethyl or a 2-alkoxyethyl group having 1 to 5 carbon atoms in the alkoxy moiety.

These new benzoquinone compounds are proved to exert an excellent antileukemic activity, for example, as studied on lymphoid leukemia L 1210 in mice and thus they can be used for human beings as a drug for the remission and treatment of various types and severities of leukemia.

They are prepared from the corresponding 1,4-benzoquinone compounds by the reaction with aziridine.

wherein R is alkyl of l to 5 carbon atoms and R is a Z-carbamoyloxyethyl group, the ethyl moiety of which may be substituted with alkyl of 1 to 5 carbon atoms or alkoxy of 1 to 5 carbon atoms at l-position or alkyl of 1 to 5 carbon atoms at 2-position; or both R, and R represent a 2-[N,N-di(alkyl)carbamoyloxy]ethyl group having 1 to 5 carbon atoms in each alkyl moiety, 2-hydroxyethyl or a 2-alkoxyethyl group having 1 to 5 carbon atoms in the alkoxy moiety. Also, it is concerned with a process for preparing the 1,4-benzoquinone compound of the above Formula I.

In the above Formula I, where the group R has a meaning different from that of R they may be separate ly exemplified by the following groups. Namely, R may be methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl United States Patent 0 and the like. The R may be carbamoyloxyethyl; l-alkoxy- Z-carbamoyloxyethyl groups, e.g. 1-methoxy-, -ethoxy-, -n-propoxy-, -n-butoxy-, or -n-pentoxy-Z-carabomyloxyethyl; 2-alkyl-2-carbamoyloxyethyl groups, e.g. 2-carbamoyloxypropyl, Z-carbamoyloxybutyl, Z-carbamoyloxypentyl, Z-carbamoyloxyhexyl or Z-carbamoyloxyheptyl; la1kyl-2-carbamoyloxyet-hyl groups, e.g. l-methyl-Z-carbamoyloxyethyl, l-ethyl-Z-carbamoyloxyethyl, l-n-propyl- Z-carbamoyloxyethyl, 1-n-butyl-2-carbamoyloxyethyl or 1- n-pentyl-Z-carbamoyloxyethyl.

Also, in the above Formula I, the group R have the same meaning as the group R wherein both the R and R may be exemplified by groups such as 2-N,N-di(alkyl)-carbamoyloxyethyl groups, e.g. 2-N,N-dimethyl-, -diethyl-, -di(npropyl)-, -di(tert-butyl)- or -di(n-pentyl)-carbamoyloxyethyl; 2-hydroxyethyl; or 2-alkoxyethyl groups, e.g. 2- methoxyethyl, 2-ethoxyethyl, 2-n-propoxyethyl, 2-i-butoxyethyl or 2-n-pentoxyethyl.

The 1,4-benzoquinone compounds (I) of this invention are new substances unknown in the prior art. They show an excellent antileukemic activity and thus they are useful as an antileukemic drug for the remission and treatment of various types and severities of leukemia.

It is, accordingly, a principal object object of this invention to provide the new 1,4-benzoquinone compound (I) which can be effectively used for the remission and treatment of leukemia.

It is another object of this invention to provide a chemical process for the preparation of such useful 1,4-benzoquinone compounds (I).

Other objects of this invention will be apparent from the following description of this invention.

A considerable number of 2,5-bis(1-aziridinyl)-l,4-benzoquinone derivatives are known in the prior art and some of them, e.g. 2,5,6-tris(l-aziridinyl)-l,4-benzoquinone, 2,5 -bis 1 -aziridinyl) -3 ,6-dimethoxy-1,4-benzoquinone and the like are found to exhibit antileukemic activity. Also, many other chemotherapeutic agents have been found and developed for the remission and treatment of leukemia in human beings.

However, more effective and safe antileukemic agents are earnestly desired in the art.

The 1,4-benzoquinone compounds of the above Formula I, have been tested on animals. The animal tests were carried out on lymphoid leukemia L 1210 in mice, substantially according to the teachings of the protocols of the Cancer Chemotherapy National Service Center in National Institute of Health, Bethesda, l4, Md., USA. Other animal tests were performed employing Ehrlich ascitestumor, Sarcoma 180, Adenocarcinoma 755 and the like. The tests indicated that the inventive compounds possess an excellent antitumor activity, resulting in a prolonged survival of test animals and, surprisingly in some cases, substantially curative effect on tumors.

Accordingly, it is apparent to those skilled in the art that the 1,4-benzoquinone compounds (I) of this invention are effective as an antileukemic drug for the remission and treatment of various types and severities of leukemia such as acute, subacute or chronic lymphatic or myelogenous leukemia in human beings.

The 1,4 benzoquinone compounds (I) of this invention may be usually administered through parenteral route, preferably by intravenous injection. The active benzoquinone compounds (I) of this invention may be employed for clinical application in various types of unit dosage forms, but it is practical and preferable to employ a single dose of the freeze-dried form of the 1,4 benzoquinone compounds (I) sealed in a suitable sterile vessel, e.g. vial and, to aseptically dissolve the content of the vessel in a suitable physiologically acceptable solvent, e.g. physiological saline, immediately prior to administration, thereby to form a liquid preparation ready for parenteral administration. A single dose of the active benzoquinone compounds (I) of this invention may be usually in the range of about 0.05 to 3 mg. and desirably about 0.1-1.5 mg. per adult per one administration. The active benzoquinone compounds (I) of this invention may be administered to those patients to be treated intermittently in proper cycles and at suitable intervals, for example, in several cycles at about one to ten days intervals and it is understood that administration should be carefully made upon proper consideration of the types and severities of leukemia, possible side efiects, toxicity and other factors.

According to this invention, there is provided a process for the preparation of the 1,4 benzoquinone compounds of the above Formula I. The process comprises reacting a 3,6-disubstituted -1,4 benzoquinone compound having the formula wherein R and R are as defined above, with aziridine.

In practising the process of this invention, the reaction may be desirably conducted by intimately contacting the starting benzoquinone (II) with aziridine in a suitable inert solvent. As a reaction solvent may be satisfactorily employed any of those solvents that are inert to and do not adversely affect the reaction of the present process. Suitable examples for solvents which may be employed include lower alkanols, e.g. methanol, ethanol or isopropanol; di(lower alkyl) ketones, e.g. acetone or methyl ethyl ketone; cyclic ethers, e.g. dioxane or tetrahydrofuran; amides, e.g. dimethylacetamide; di(lower alkyl)- sulfoxides, e.g. dimethyl sulfoxide; aqueous lower alkanols, e.g. aqueous methanol, ethanol or isopropanol; aqueous di(lower alkyl)ketones, e.g. aqueous acetone or tetrahydrofuran; aqueous cyclic ethers, e.g. aqueous dioxane or tetrahydrofuran; and the like. Preferred are lower alkanols. The reaction temperature is not critical in the present process, but it is usual and preferable to conduct the reaction at room temperature or below. Higher temperatures may, of course, be applied although these do not result in any further advantages. Also, the reaction period is not critical and may vary over a wide range mainly depending upon the kind of the starting material employed. Usually, it requires from several hours to several days to bring the reaction to completion.

Alternatively, the reaction in the present process may be satisfactorily carried out in the presence of a cupric salt of an inorganic or organic acid, for example, cupric sulfate or cupric acetate under oxygen atmosphere thereby leading to better results, e.g. higher yield of the desired product, since more eificient utilization of the starting benzoquinone compound (II) in the reaction may be accomplished because of oxidative conversion of the corresponding hydroquinone by-product (resulting from the reaction of the starting benzoquinone compound (II) with aziridine) into the starting benzoquinone compound (II).

After completion of the reaction, the reaction product (I) may be recovered from the reaction mixture by a conventional means. For instance, the crystalline final product precipitated in situ may be recovered by filtration and, if necessary, the product thus obtained may be further purified by recrystallization from a suitable solvent, e.g. ethanol.

The 1,4-benzoquinone compounds of the above formula (II) which may be employed as a starting material in the present process are new chemical substances with the exception of the 1,4-benzoquinone compound of the formula (II) wherein both the R; and R are 2-hydroxyethyl group.

Such new starting benzoquinone compounds may be easily prepared by the following ways:

(a) The 1,4-benzoquinone compounds (II) wherein the R is alkyl of 1 to 5 carbon atoms and R is a 2-carbamoyloxyethyl group, the ethyl moiety of which may be substituted with alkyl of 1 to 5 carbon atoms or alkoxy of 1 to 5 carbon atoms at l-position or alkyl of 1 to 5 carbon atoms at 2-position, may be prepared by reacting a hydroquinone compound having the formula (i011; (III) wherein R is alkyl of 1 to 5 carbon atoms and R is a 2-hydroxyethyl group, the ethyl moiety of which may be substituted with alkyl of 1 to 5 carbon atoms or alkoxy of 1 to 5 carbon atoms at l-position or alkyl of 1 to 5 carbon atoms at 2-position with phosgene or an aryl chloroformate followed by reaction with ammonia to form a hydroquinone dimethyl ether having the formula (I)CH OCH;

wherein R is as defined above and R is a Z-carbamoyloxyethyl group, the ethyl moiety of which may be substituted with alkyl of 1 to 5 carbon atoms or alkoxy of 1 to 5 carbon atoms at l-position or alkyl of 1 to 5 carbon atoms at 2-position and then oxidizing the latter ether (IV) with nitric acid.

(b) The 1,4-benzoquinone compounds (II) wherein both the R and R represent a 2-alkoxyethyl group having 1 to 5 carbon atoms in the alkoxy moiety may be prepared by reacting 2,5 bis(2-hydroxyethyl)-hydroquinone dimethyl ether with an alkyl iodide followed by oxidation with nitric acid.

(0) The 1,4-benzoquinone compounds (II) wherein both the R and R represent a 2-[N,N-di(alkyl) carbamoyloxy] ethyl group having 1 to 5 carbon atoms in each alkyl moiety may be prepared by reacting 2,5-bis(2-hydroxyethyl)-hydroquinone dimethyl ether with phosgene or an aryl chloroformate followed by reaction with a dialkyl amine to form a hydroquinone dimethyl ether having the formula OCH EXAMPLE 1 Preparation of 2,5-bis( l-aziridinyl)-3-(2-carbamoyloxyethyl)-6-methyl-1,4-benzoquinone To a solution of 1 g. of 2-methyl-5-(Z-carbamoyloxyethy1)-1,4-benzoquinonc in ml. of ethanol was added 1 ml. of aziridine. The resulting mixture was allowed to stand at room temperature for 4 days. The crystalline substance which precipitated in situ was recovered by filtration and then recrystallized from ethanol to give 0.3 g. of the desired product as reddish orange crystals melting at 196 C. (with decomposition).

Analysis.Calculated for C H O N (percent): C, 57.72; H, 5.88; N, 14.43. Found (percent): C, 57.54; H, 6.09; N, 14.50.

EXAMPLE 2 Preparation of 2,5-bis( 1-aziridinyl)-3-( 1-methoxy-2 carbamoyloxyethyl) -6-methyl-1,4-benzoquinone In 10 ml. of ethanol was dissolved with heating 200 mg. of 2 methyl (1-methoxy-2-carbamoyloxyethyl)- 1,4-benzoquinone and the resulting solution was cooled. To the cooled solution was added 0.5 ml. of aziridine and then the resulting mixture was allowed to stand in a refrigerator at 58 C. for 4 days. Thereafter, the crystalline substance which precipitated in situ was recovered by filtration and washed with ethanol to give 50 mg. of the desired product as red crystals melting at 200 C. (with decomposition).

Analysis.-Calculated for C H O N (percent): C, 56.06; H, 5.96; N, 13.08. Found (percent): C, 55.94; H, 6.15; N, 13.11.

EXAMPLE 3 Preparation of 2,5-bis( 1-aziridinyl)3-(2-carbamoyloxypropyl -6-methyll ,4-benzoquinone To a solution of .230 mg. of 2-methyl-5-(2-carbamoyloxypropyl)-1,4-benzoquinone in 4 ml. of ethanol was added 0.2 ml. of aziridine. The resulting mixture was allowed to stand at room temperature for 4 hours and then in a refrigerator for additional 2 days. The crystalline substance which precipitated in situ was recovered by filtration and then recrystallized from ethanol to give 80 mg. of the desired product as reddish orange needles melting at 183 C.

Analysis.Calculated for C H O.,N (percent): C, 59.00; H, 6.27; N, 13.76. Found (percent): C, 59.19; H, 6.23; N, 13.51.

EXAMPLE 4 Preparation of 2,5-bis( l-aziridinyl)-3-(1-ethoxy-2-carbamoyloxyethyl) -6-methyl-1,4-ben2oquinone To a solution of 0.5 g. of 2-methyl-5-(1-ethoxy-2- carbamoyloxyethyl)-1,4-benzoquinone in ml. of ethanol was added 0.5 ml. of aziridine. The resulting mixture was allowed to stand at room temperature for 2 days. The crystalline substance which precipitated in situ was recovered by filtration and then recrystallized from ethanol to give 0.1 g. of the desired product as reddish orange crystals melting at 199 C. (with decomposition).

Analysis.--Calculated for C H O N (percent): C, 57.30; H, 6.31; N, 12.53. Found (percent): C, 57.31; H, 6.28; N, 12.39.

Following the same procedure as described above, the 2,5-bis(1-aziridinyl)-l,4 benzoquinones were similarly obtained from the corresponding 1,4-benzoquinones:

2,5 bis(1 aziridinyl) 3 (1-methoxy-2-carbamoyloxyethyl) 6 ethyl-1,4-benzoquinone, reddish orange crystals (M.P. 148 C.),

Analysis.Calculated for C H O N (percent): C, 57.30; H, 6.31; N, 12.53. Found (percent): C, 57.10; H, 6.39; N, 12.52.

and 2,5 bis(1 aziridinyl) 3 (2-carbarnoyloxyethyl)- 6-ethyl-1,4-benzoquinone, reddish orange crystals (M.P. 184 C.),

Analysis.Calculated for C H O N (percent): C, 59.00; H, 6.27; N, 13.76. Found (percent) C, 59.44; H, 6.61; N, 13.67.

6 EXAMPLE 5 Preparation of 2,5-bis(l-aziridinyl)-3-(2-carbamoyloxyethyl) -6-n-propyl-1,4-benzoquinone To a solution of 1 g. of 2-n-propyl-5-(Z-carbamoyloxyethyl)-1,4-benzoquinone in 20 ml. of ethanol was added 1 ml. of aziridine. The resulting mixture was allowed to stand at room temperature for 2 days. Thereafter, the ethanol was distilled off under a reduced pressure and the residue was recrystallized from ethanol to give 0.2 g. of the desired product as reddish orange crystals melting at 176 C.

Analysis.-Calculated for C H O N (percent): C, 60.17; H, 6.63; N, 13.16. Found (percent): C, 60.60; H, 6.85; N, 13.59.

EXAMPLE 6 Preparation of 2,5-bis(1-aziridinyl)-3,6-bis(2- methoxyethyl)-1,4-benzoquinone To a solution of 0.5 of 2,5-bis(2-methoxyethyl)-l,4- benzoquinone in 5 m1. of ethanol was added 0.3 ml. of aziridine. The resulting mixture was allowed to stand overnight at room temperature. The crystalline substance which precipitated in stiu was recovered by filtration and then recrystallized from ethanl to give the desired product as reddish orange crystals melting at 144 C.

Analysis.Calculated for C H O N (percent): C, 62.72; H, 7.24; N, 9.14. Found (percent): C, 62.63; H, 7.50; N, 9.45.

Alternatively, to a mixture of 2 g. of a cupric acetate powder, 50 ml. of methanol and 2 ml. of aziridine was added dropwise with continuous oxygen gas bubbling a solution of 2 g. of 2,5-bis(Z-methoxymethyl)benzoquinone in 20 ml. of methanol, while stirring and maintaining the inner temperature of the reaction system at 20-30" C. After completion of the dropwise addition, oxygen gas bubbling was continued for further 2.5 hours with stirring at room temperature. Then, the solvent was removed from the reaction mixture under a reduced pressure at room temperature. The residue was extracted into several portions of chloroform, the combined extracts were dried over anhydrous sodium sulfate and the chloroform was removed by distillation. Upon recrystallization of the crystalline substance from ethanol, there was obtained the desired product (melting at 144 C.), which was identified with that obtained in the foregoing by a mixed melting point depression.

EXAMPLE 7 Preparation of 2,5-bis(1-aziridinyl)-3,6-bis(2- hydroxyethyl) 1,4-benzoquinone To a solution of 0.9 g. of 2,5-bis(2-hydroxyethyl)-1,4- benzoquinone in 5 m1. of ethanol was added 0.5 ml. of aziridine. The resulting mixture was allowed to stand overnight in a refrigerator at about 5 C. The crystalline substance which precipitated in situ was recovered by filtration and then recrystallized from ethanol to give the desired product as reddish brown crystals melting at C. (with decomposition).

Analysis.Calculated for C H O N (percent): C, 60.42; H, 6.52; N, 10.07. Found (percent): C. 60.57; H, 6.79; N, 10.19.

EXAMPLE 8 Preparation of 2,5-bis( l-aziridinyl) 3,6-bis [2- (N,N,dimethylcarbamoyloxy ethyl] 1,4-benzoquinone To a solution of 0.5 of 2,5-bis[2-(N,N-dimethylcarbamoyloxy)ethyl]-1,4-benzoquinone in 10 ml. of ethanol was added 0.3 ml. of aziridine. The resulting mixture was allowed to stand at room temperature for 5 hours. The crystalline substance which precipitated in situ was recovered by filtration. To the substance thus obtained was added 10 ml. of chloroform and, after weak stirring, insoluble substance was removed by filtration. Then, under a reduced pressure, the solvent was distilled off from the filtrate and the residue was recrystallized from ethanol to give the desired product as reddish brown needles melting at 175 C.

Analysis.Calculated for C H O N (percent): C, 57.13; H, 6.71; N. 13.33. Found (percent): C, 56.89; H, 5 6.75; N, 13.48.

What is claimed is:

1. A compound having the formula wherein R is an alkyl group of 1 to 5 carbon atoms and R is a Z-carbamoyloxyethyl group, the ethyl moiety of which may be substituted with an alkyl group of 1 to 5 carbon atoms or an alkoxy group of 1 to 5 carbon atoms at l-position or an alkyl group of 1 to 5 carbon atoms at 2-position; or both R and R represent a 2- [N,N-di(alky1)carbamoyloxy] ethyl group having 1 to 5 carbon atoms in each alkyl moiety, Z-hydroxyethyl group or a 2-alkoxyethyl group having 1 to 5 carbon atoms in the alkoxy moiety.

2. 2,5 bis(l aziridinyl) 3 (l methoxy 2- carbamoyloxyethyl)-6-methyl-1,4-benzoquinone.

3. 2,5 bis(l aziridinyl) 3 (l ethoxy 2- carbamoyloxyethyl)-6-methyl-1,4-benzoquinone.

4. 2,5 bis(l aziridinyl) 3 (l methoxy 2- carbamoyloxyethyl)-6-ethyl-1,4-benzoquinone.

5. 2,5 bis(l aziridinyl) 3 (2 carbamoloxypropyl)-6-methyl-1,4-benzoquinone.

6. 2,5 bis(l aziridinyl) 3 (2 carbamoyloxyethyl)-6-methyl-1,4-benzoquin0ne.

7. 2.5 bis(l aziridinyl) 3 (2 carbamoyloxyethyl)-6-ethyl-1,4-benzoquinone.

8. 2,5 bis(l aziridinyl) 3,6 bis[2 (N,N-dimethylcarbamoyloxyethyl]-1,4-benzoquinone.

9. 2,5 bis(l aziridinyl) 3,6 bis(2 hydr0xyethyl)- 1,4-benzoquinone.

10. 2,5 bis(l aziridinyl) 3,6 bis(2 methoxyethyl) 1,4-benzoquinone.

References Cited FOREIGN PATENTS 191,877 9/1957 Austria 260-239 ALTON D. ROLLINS, Primary Examiner US. Cl. X.R. 

